Prognostic Value of Tryptophan Load Test Followed by Serum Kynurenine Determination. It’s Comparison With Pyridoxal-5-phosphate, Kynurenine, Homocysteine and Neopterin Amounts

Rudzite, Vera; Fuchs, Dietmar; Kalnins, Uldis; Jurika, Edite; Silava, Anita; Ērglis, Andrejs; Trušinskis, Kārlis; Jēgere, Sanda

doi:10.1007/978-1-4615-0135-0_34

Cited by 7 publications

(5 citation statements)

References 27 publications

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“…Vitamin B6 depletion resulted in drastic increase while vitamin B6 supplementation normalized urinary 3-HK and XA after TRP load in cardiac [15] and obese [16] patients and rats [17]. Therefore, P5P deficiency combined with up-regulation of TRP – KYN pathway might divert KYN – NAD metabolism towards increased formation of XA at the expense of NAD production (Fig.1).…”

Section: Pyridoxal 5′-phosphate and Kyn – Nad Metabolic Pathwaymentioning

confidence: 99%

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

2013

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Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders (AAMPD). Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of literature and our data presents the evidences that dysregulation of tryptophan (TRP) – kynurenine (KYN) and KYN – nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. First and rate-limiting step of TRP – KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN – NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a co-factor. Deficiency of P5P diverts KYN – NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced up-regulation of TRP – KYN metabolism in combination with P5P deficiency-induced diversion of KYN – NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects-at-risk for IR. Pharmacological regulation of the TRP – KYN and KYN – NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress–induced excessive production of KYN and deficiency of vitamin B6, e.g., diabetes type 2, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.

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Section: Pyridoxal 5′-phosphate and Kyn – Nad Metabolic Pathwaymentioning

confidence: 99%

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

2013

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“…In rodents, tissue Trp concentrations have been reported to vary from ~ 1/3 (muscle) to 2.6 times (kidney) the plasma Trp concentration [70], with the latter ranging from 15 to 40 μ m [70–72]. The reference value for plasma Trp in healthy humans is 50–90 μ m [73–75]. In mice, deficiency in tryptophan 2,3‐dioxygenase (TDO, http://www.chem.qmul.ac.uk/iubmb/enzyme/EC%A01/13/11/11.html) increases the concentration of Trp in plasma and tissues 10‐ to 20‐fold [71,72].…”

Section: Discussionmentioning

confidence: 99%

Methylene blue and ascorbate interfere with the accurate determination of the kinetic properties of IDO2

Yuasa

Stocker

2021

The FEBS Journal

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Indoleamine 2,3‐dioxygenases (IDOs) catalyze the oxidative cleavage of L‐tryptophan (Trp) to N‐formylkynurenine. Two IDOs, IDO1 and IDO2, are present in vertebrates. IDO1 is a high‐affinity Trp‐degrading enzyme involved in several physiological processes. By comparison, IDO2 generally has been reported to have low affinity (high Km‐value) for Trp, and the enzyme's in vivo function remains unclear. Using IDOs from different species, we show that compared with ferrous‐oxy (Fe2+–O2) IDO1, Fe2+–O2 IDO2 is substantially more stable and engages in multiple turnovers of the reaction in the absence of a reductant. Without reductant, Fe2+–O2 IDO2 showed Km‐values in the range of 80–356 μM, that is, values substantially lower than reported previously and close to the physiological concentrations of Trp. Methylene blue and ascorbate (Asc), used commonly as the reducing system for IDO activity determination, significantly affected the enzymatic activity of IDO2: In combination, the two reductants increased the apparent Km‐ and kcat‐values 8‐ to 117‐fold and 2‐fold, respectively. Asc alone both activated and inhibited IDO2 by acting as a source of electrons and as a weak competitive inhibitor, respectively. In addition, ferric (Fe3+) IDO1 and IDO2 exhibited weak dioxygenase activity, similar to tryptophan 2,3‐dioxygenase. Our results shed new light in the enzymatic activity of IDO2, and they support the view that this isoform of IDO also participates in the metabolism of Trp in vivo.

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“…Vitamin B6 depletion drastically increased while vitamin B6 supplementation normalized urinary HK and 3-HKYNA excretion after TRP load in cardiac (Rudzite et al 2003 ) and obese patients (Yess et al 1964 ) and rats (Okamoto 2003 ). In addition, vitamin B6 dose-dependently decreased insulin levels and improved insulin sensitivity in the KK-A(y) mice, animal model of type 2 diabetes (Murakoshi et al 2009 ;Unoki-Kubota et al 2010 ).…”

Section: Regulation Of Downstream Kyn Metabolic Pathwaysmentioning

confidence: 92%

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

Oxenkrug

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Aging, obesity, depression, Parkinson's and other neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs are highly associated with insulin resistance (IR) and type 2 diabetes mellitus (T2D). Molecular mechanisms of increased associations remain uncertain. Current review of literature and our data suggest that one such mechanism is the overproduction of diabetogenic factors resulting from dysregulation of upstream and downstream pathways of tryptophan (TRP)-kynurenine (KYN) metabolism. Proinfl ammatory factors and stress hormones activate two upstream steps of TRP-KYN pathway: TRP conversion into KYN, a substrate for formation of kynurenic acid (KYNA), and KYN conversion into 3-hydroxyKYN (3-HK). The fi rst step of downstream pathway of 3-HK metabolism, formation of 3-hydroxyanthranilic acid (3-HAA), is catalyzed by pyridoxal-5-phosphate (P5P)-dependent kynureninase (KYNase). P5P defi ciency, associated with infl ammation, stress, and treatment with antipsychotic drugs, diverts metabolism of overproduced 3-HK from formation of 3-HAA to the excessive formation of 3-hydroxykynurenic acid (3H-KYNA). Human and experimental studies suggested diabetogenic (e.g., impairment of production, release, and biological activity of insulin) effect of KYN, 3H-KYNA, KYNA, and their metabolites. We propose that one of the mechanisms of increased association of IR (and T2D) with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs is overproduction of 3H-KYNA resulting from upregulated formation of 3-HK augmented by P5P defi ciency. Pharmacological regulation of upand downstream TRP-KYN metabolic pathways might be a new approach for prevention and treatment of IR (and IR progression to T2D) associated with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs.

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Prognostic Value of Tryptophan Load Test Followed by Serum Kynurenine Determination. It’s Comparison With Pyridoxal-5-phosphate, Kynurenine, Homocysteine and Neopterin Amounts

Cited by 7 publications

References 27 publications

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

Methylene blue and ascorbate interfere with the accurate determination of the kinetic properties of IDO2

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

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